Caratteristiche cliniche e patologiche del carcinoma differenziato della tiroide, sono veramente cambiate nel corso degli ultimi 35 anni?

S P E C I A L F E A T U R E

E x t e n s i v e C l i n i c a l E x p e r i e n c e

Are the Clinical and Pathological Features of
Differentiated Thyroid Carcinoma Really Changed
over the Last 35 Years? Study on 4187 Patients from
a Single Italian Institution to Answer this Question

Rossella Elisei,* Eleonora Molinaro,* Laura Agate, Valeria Bottici, Lucio Masserini,
Claudia Ceccarelli, Francesco Lippi, Lucia Grasso, Fulvio Basolo,
Generoso Bevilacqua, Paolo Miccoli, Giancarlo Di Coscio, Paolo Vitti, Furio Pacini,
and Aldo Pinchera
Departments of Endocrinology and Metabolism (R.E., E.M., L.A., V.B., C.C., F.L., L.G., P.V., A.P.), Surgery
(F.B., P.M.), Oncology (Division of Pathology) (G.B., G.D.C.), and Statistics and Applied Mathematics to
Economy (L.M.), University of Pisa, 56100 Pisa, Italy; Departments of Internal Medicine, Endocrinology and
Metabolism, and Biochemistry (F.P.), University of Siena, 53100 Siena, Italy; World Health Organization
Collaborating Center for the Diagnosis and Treatment of Thyroid Cancer and Other Thyroid Diseases (R.E.,
E.M., L.A., V.B., C.C., F.L., L.G., P.V., A.P.); and AMBISEN Center (A.P.), High Technology Center for the
Study of the Environmental Damage of the Endocrine and Nervous Systems, University of Pisa, 56124 Pisa,
Italy

Background: In the last decades, a marked increased prevalence of differentiated thyroid cancer
(DTC) has been observed worldwide. The aim of this study was to evaluate the changing features
of DTC referred to our institution between 1969 and 2004.

Methods: Clinical and pathological features and prognostic factors were analyzed in 4187 DTC
patients, subdivided into two groups: group 1 (n 1215) and group 2 (n 2972) diagnosed before
and after 1990, respectively.

Results: Group 2 showed an increased proportion of micropapillary carcinoma and a concomitant
decrease of follicular histotype. Male percentage was greater in group 2, whereas median age at
diagnosis was unchanged. DTC of group 2 were more frequently associated with multinodular
goiter or autoimmune thyroiditis, but many were unexpected findings. Features of aggressiveness
were significantly less frequent in group 2, and the survival rate was greater (98.7 vs. 91.4%, P
0.0001). Gender, age, histotype, tumor size, extrathyroidal macroinvasion, and lymph node and/or
distant metastases were found to be poor prognostic factors in both groups using univariate
analysis, but with multivariate analysis, only advanced age (odds ratio 22.52 for older patients)
and advanced stage (odds ratio 53.54 for more advanced cases) were independently correlated
with a lower survival.

Conclusions: DTC patients diagnosed after 1990 have smaller tumors with less advanced stage and
a better prognosis. The question of whether this is related to the finding of tumors with a low
clinical penetrance or to the anticipation of diagnosis remains to be clarified. Despite these sig-
nificant differences, both advanced stage and older age still represent the most important poor
prognostic factors for survival. (J Clin Endocrinol Metab 95: 1516 –1527, 2010)

ISSN Print 0021-972X ISSN Online 1945-7197 Abbreviations: DTC, Differentiated thyroid cancer; FNA, fine-needle aspiration; FTC, fol-
Printed in U.S.A. licular variant of PTC; IRMA, immunoradiometric assay; mPTC, micro-PTC; OR, odds ratio;
Copyright © 2010 by The Endocrine Society PTC, papillary thyroid carcinoma; Tg, thyroglobulin; TgAb, anti-Tg antibodies; TNM, tumor-
doi: 10.1210/jc.2009-1536 Received July 20, 2009. Accepted January 8, 2010. node-metastases; WBS, whole-body scan.
First Published Online February 15, 2010
* R.E. and E.M. equally contributed to this paper.

1516 jcem.endojournals.org J Clin Endocrinol Metab, April 2010, 95(4):1516 –1527

J Clin Endocrinol Metab, April 2010, 95(4):1516 –1527 jcem.endojournals.org 1517

n the last few years, a relevant increased incidence of Patients and Methods
I thyroid cancer has been documented worldwide (1–
10). Epidemiological studies in the United States demon- Patients
The study group consisted of 4187 patients (3166 females and
strated that, in the last 5 yr, the thyroid cancer rate of 1021 males, 3:1 ratio) ranging in age from 5– 88 yr (mean 42.4
incidence has been the highest among all tumors (11). The yr 14.4 yr, median 42 yr). A total of 3684 (88%) patients had
increased number of cases is mainly due to small papillary PTC, and 503 (12%) had a follicular thyroid cancer (FTC), in-
thyroid carcinoma (PTC) (1–3, 6, 10), which is typically cluding Huerthle cell variant. Poorly differentiated, anaplastic,
and medullary thyroid carcinomas were not included in the
well differentiated and curable (12–15).
study.
The Department of Endocrinology at the University The mean follow-up was 9 7.6 yr, ranging from 0.5–34.5
Hospital of Pisa is a national referral center for the diag- yr (median, 7 yr). A scheduled annual visit for clinical and bio-
nosis and treatment of thyroid cancer. From 1969 to date, chemical control generally guarantees keeping the majority of
patients under active follow-up. When such controls were not
almost 8000 thyroid cancer (all histotypes) have been reg-
performed, patients were contacted directly or through their
istered at this institution. In the present study, we focused family doctor. As a result, at the time of this analysis, the clinical
our attention on a group of 4187 consecutive differenti- outcome of 3952 of 4187 patients (94.4%) was known with only
ated thyroid cancer (DTC) patients having at least a 3-yr 235 of 4187 lost patients (5.6%).
follow-up. To our knowledge, this is the largest series of As common practice, patients have been requested to sign an
informed consent to the collection of clinical and pathological
DTC patients followed at one single institution. The series data. The present study has been approved by the Internal Re-
is characterized by a considerable homogeneity in treat- viewing Board of the Department of Endocrinology and Metab-
ment and follow-up strategies, a very low percentage of olism of the University of Pisa.
patients lost at follow-up ( 6%), and an almost unique
long-term follow-up, with more than 500 patients fol- Management of DTC patients
lowed for more than 20 yr. Since 1969, most of the same endocrinologists, endocrine
surgeons, nuclear medical physicians, and pathologists has been
Clinical and pathological features of DTC in patients
involved in the management of DTC patients. Strict collabora-
diagnosed before and after the year 1990 were separately tion and shared protocols helped to maintain uniform treatment
analyzed and compared. The rationale to distinguish the and follow-up strategies.
two groups before and after 1990 derived from the ob- Initial treatment included a near-total thyroidectomy fol-
servation that around this time period, a sharp and pro- lowed by radioiodine (131I) ablation (100 mCi before 1980, 30
mCi thereafter) of postsurgical thyroid remnant. Patients re-
gressive increase in the number of patients referred to our ferred after initial surgery were submitted to completion thy-
institution occurred (Fig. 1) in conjunction with the wide- roidectomy if the first operation had been less than a near-total
spread use of neck ultrasound for diagnostic procedures in thyroidectomy.
our country (16). The study hypothesis was that the two Patients with metastatic disease underwent additional treat-
ments consisting of 131I therapeutic doses (100 –200 mCi) until
groups should be characterized by a different biological
the evidence of a negative posttherapeutic whole-body scan
and clinical behavior. The results of this analysis have been (WBS). Whenever necessary, the 131I treatments were repeated at
discussed in the present report. interval times not shorter than 6 months. Neck recurrences and
single lung or bone metastases were treated by surgery whenever
technically possible. Neck external radiotherapy was indicated after
an incomplete surgical treatment due to local infiltration or re-
peated relapses in the neck. Bone radiotherapy was used for pain
control. Chemotherapy was administered in patients with systemic
metastatic disease who did not respond to radioiodine any longer.
All patients were submitted to L-T4 therapy. Tailored TSH-
suppressive doses were administered until evidence of a disease-
free status. Partially suppressive or substitutive doses were given
thereafter.

Follow-up strategy
The first postthyroid remnant ablation control was per-
formed after 3– 6 months. The follow-up controls were sched-
uled every 12 months and consisted of clinical and laboratory
FIG. 1. Number of patients with DTC observed over the years
1969 –2004 at the Thyroid Cancer Center of the Department of
evaluation on L-T4 therapy, including free thyroid hormones,
Endocrinology, University Hospital of Pisa, after it was established in TSH, thyroglobulin (Tg) (from 1976) and anti-Tg antibodies
1969. The number of referred patients linearly increased over the (TgAb) measurements. In 1989, neck ultrasound was routinely
years, whereas a sharp unexpected increase occurred between the introduced in the follow-up of DTC patients. When a suspicious
late 1980s and early 1990s. lymph node was found, fine-needle aspiration (FNA) cytology

1518 Elisei et al. Single-Institution 35-Year Study on 4187 Patients J Clin Endocrinol Metab, April 2010, 95(4):1516 –1527

and Tg measurement in the needle washout were performed (17). Incstar Corp., Stillwater, MN) was used up until 1988, a more
Other imaging techniques were carried out when needed. sensitive method (hTSH Ultra; Delfia, Wallace Oy, Finland) was
In 2001, the recombinant human TSH-Tg stimulation test employed up until 1996, and the ultrasensitive immunochemilu-
was introduced in our department to ascertain the persistence of minescent assay method (Diagnostic Products) has been used since.
the disease (18, 19). A diagnostic WBS was performed only when Urinary iodine content was measured with the UV irradiation
high titers of TgAb were detected. method (28) employing an automated autoanalyzer (Bran-Lu-
ebbe S.P.A., Gallarate, Italy).
Pathology 131
I WBS
Because our department is a national referral center, almost
Until 1997, the postsurgical thyroid remnant 131I ablation
half of the DTC patients [2344 of 4187 (52.1%)] were referred
was preceded by a diagnostic 1-mCi WBS. Since 1997, a 50- Ci
after initial surgery. All cases operated on at the University Hos-
thyroid bed radioiodine uptake measurement (New Atomlab
pital of Pisa have been analyzed by the same team of pathologists.
950; Biodex Medical System, Urbino, Italy) was substituted for
Starting from 1990, the histological slides of patients referred
the diagnostic WBS and a 3- to 7-d post-131I-ablation WBS was
after surgery were routinely reexamined by our endocrine pa-
routinely performed.
thologists. The histological slides of DTC diagnosed before 1990
After remnant 131I ablation, patients were followed with a
were revised when available.
yearly control of serum Tg and 4- to 5-mCi diagnostic 131I WBS
Histopathological examination and classification were car-
while hypothyroid (TSH 30 U/ml). A therapeutic dose of 131I
ried out following the morphological criteria used at the time of
was administered whenever serum Tg was detectable and/or the
observation (20, 21). Whenever requested, immunohistochem-
diagnostic WBS was positive. After 1998, the diagnostic WBS
istry for Tg or other relevant proteins was performed. Tumor
was no longer performed, and patients directly underwent 131I
size, foci number, local extrathyroidal extension, and the pres-
therapy when basal or TSH-stimulated serum Tg, either by en-
ence of metastatic lymph nodes were reported and used for
dogenous or exogenous TSH, was detectable. A posttherapeutic
tumor-node-metastases (TNM) classification (22).
WBS was performed 1–5 d after the 131I treatment.
Over the last 30 yr, three major changes have occurred in the
The WBS was performed using a rectilinear scanner up until
practice of thyroid pathology. 1) The follicular variant of PTC
1995, a one-head camera (Apex SPX 4000, Elscint, Milano,
was recognized and introduced in the thyroid tumor classifica-
Italy) with a higher energy collimator up until 2000 and a double-
tion (23, 24). The patients treated before these changes were
head camera (Axis/Iris, Marconi Medical System, Cleveland,
reclassified whenever their histological slides could be traced.
OH) with high-energy collimators thereafter.
This was possible for the majority of patients submitted to sur-
gery in Pisa (i.e. 41 of 49 FTC) but for only a minority of those Neck ultrasound
referred after surgery (i.e. 20 of 78 FTC). 2) The sampling col-
At our center, neck ultrasound was routinely introduced in
lection method was changed. Only one sample of apparently
the work-up of patients with any type of thyroid disease, starting
normal thyroid tissue was prepared up until 1990, whereas sev-
from 1986. In particular, DTC patients were submitted to neck
eral 3- to 4- m sections were prepared thereafter, and the pos-
ultrasound at any follow-up control. Central, laterocervical, and
sibility of recognizing microscopic tumor foci was increased. 3)
supraclavear nodes compartments were evaluated on a routine
In 2002, the new sixth edition TNM staging was introduced in
basis by the endocrinologist who was visiting the patient.
the clinical practice (22).
As a staging system, we used the De Groot’s classification Disease-free, recurrence, and persistence
(25), which is based on the combination of clinical, surgical, and
Patients were considered disease-free when WBS was negative
pathological data. Differently from the TNM staging, the De
and both endogenous or exogenous TSH-stimulated Tg and
Groot’s classification does not take into account the age of the
TgAb were undetectable (29). The recurrence was defined as the
patient at the time of diagnosis.
evidence of the disease at least 6 months after the definition of a
disease-free status.
Biochemical tests Patients with detectable levels of serum Tg or elevated titers
In 1976, serum Tg measurement became the routine test for of TgAb were not defined as disease-free but with persistence,
the follow-up of DTC patients. From 1976 –1982, it was mea- even if both WBS and other imaging techniques were unable to
sured by a homemade RIA, whereas from 1982–1998 by a com- detect any lesion (i.e. biochemical persistence).
mercial immunoradiometric assay (IRMA) (Sorin, Saluggia, It-
aly). In both cases, the sensitivity was 3 ng/ml. A more sensitive Data analysis
solid-phase chemiluminescent IRMA with a functional sensitiv- Clinical data are presented with descriptive statistical analy-
ity of 0.9 ng/ml was adopted in 1998 (Immulite 2000; Diagnostic sis. Statistical analysis was performed using Mann-Whitney U
Products Corp., Los Angeles, CA). and 2 tests according to the data to be analyzed. Survival curves
To avoid misinterpretation of Tg measurements, patients were plotted by the Kaplan-Mayer method with the log rank
were routinely screened for TgAb (26, 27). The TgAb measure- statistic. P values 0.05 were considered significant. Multivar-
ment was performed by passive hemagglutination up until 1990 iate analysis was performed using a Cox regression model.
(thyroid test kit; Fujizoki, Fujirebio Inc., Tokyo, Japan), by
IRMA up until 2000 (ICN Pharmaceutical, High Wycombe, UK)
and by an immunoenzymometric assay (AIA PACK TgAb Sys- Results
tem; Tosoh Bioscence, Tessenderlo, Belgium) thereafter.
TSH measurement was performed using different methods Gender, age, and histotype observed in the study groups
with increasing sensitivity. A RIA (clinical assay -coat hTSH; are reported in Table 1. The comparison of these features


TABLE 1. Epidemiological and histological data of patients with DTC referred to University Hospital of Pisa from
1969 –2004
Total series 1969 –1989, group 1 1990 –2004, group 2 P (group 1 vs. group 2)
No. of patients 4187 1215 (29.0%) 2972 (71.0%)
Sex
Female (n) 3166 (75.6%) 944 (77.7%) 2222 (74.8%) 0.04
Male 1021 (24.4%) 271 (22.3%) 750 (25.2%)
Age at diagnosis (yr) 42.5 14.4 (5– 88) 42.2 15.8 (5– 84) 42.6 13.9 (7– 88) NS (0.56)
Histotype
Papillary cancer (PTC) 3684 (88%) 979 (80.5%) 2705 (91.0%) 0.0001
Follicular cancer (FTC) 503 (12%) 236 (19.5%) 267 (9.0%)
Data were analyzed in the entire group (total series) and separately in patients diagnosed before 1990 (group 1) and after 1990 (group 2). Median
age for total series and both groups was 42 yr. The FTC group includes Huerthle cells carcinoma. NS, Not significant.

showed that, as expected, the vast majority of patients ing diagnostic procedures, usually neck ultrasound, per-
were female in both groups. There was, however, a sig- formed for reasons other than thyroid disease. The inci-
nificant albeit small increase of males, from 22% in group dental finding of a nodule was declared as the reason for
1 to 25% in group 2. The mean age at diagnosis was 42.5 referral by 16% of the total cases, with a significant in-
yr, with no difference between the two groups. A PTC crease from 8% in group 1 to 20% in group 2. The finding
diagnosis accounted for the majority of patients in both of suspicious cervical nodes occurred in nearly 10% of the
groups. However, a significant reduction of FTC, from total series with a sharp decrease from 17% in group 1 to
19.5% in group 1 to 9.0% in group 2 was observed. 7% in group 2. Local symptoms such as pressure and/or
As shown in Table 2, 63.6% of the total series did not dysphagia and/or dysphonia, were reported in a minority
show a coexisting thyroid disease, and this percentage de- of patients (3.4%), with a significant decrease from 5% in
creased from 72.6% in group 1 to 59.8% in group 2. group 1 to 2.6% in group 2. Hyperthyroidism was the
Nodular goiter was the most frequent coexisting disorder. presenting symptom only in approximately 2.5% of sub-
It was found in 26% of the total series and was signifi- jects with no difference between the two groups. Only few
cantly more frequent in group 2 than group 1 (27.5% vs. patients arrived at the diagnosis for bone pain or other
22.3%). Autoimmune thyroiditis accounted for 7.5% of signs of distant metastases, but nevertheless, a significant
coexisting disorders in all subjects, with an interesting in- reduction from group 1 to group 2 (1.8 vs. 0.5%) was
crease from 2.0% in group 1 to 9.8% in group 2. Graves’ observed.
disease and toxic adenoma accounted only for a minority Pathological features are reported in Table 4. Small
of coexisting diseases with no difference between the two tumors smaller than 1 cm showed a sharp increase from
groups. A positive history of neck irradiation was found in 7.9% in group 1 to 28.7% in group 2. In contrast, a
3.2% of the total series with a significant drop from 6.1% significant decrease in the percentage of tumors larger
in group 1 to 1.9% in group 2. than 1 cm was observed in group 2. In particular, tu-
The presence of a thyroid nodule was the most fre- mors of 4 cm or more accounted for 13.3% of the total
quently reported presenting symptom (66.8%) with no series, with a significant decrease from 17.4% in group
difference between the two groups (Table 3). A thyroid 1 to 11.8% in group 2. Local extrathyroidal extension
nodule was listed as an incidental finding if detected dur- due to microinvasion of surrounding tissues (i.e. T3 in

TABLE 2. Prevalence of coexisting thyroid diseases in the entire group (total series) and in patients diagnosed before
1990 (group 1) and after 1990 (group 2)
No. of patients 4187 1215 2972
Coexisting thyroid diseases (n)
None 2661 (63.6%) 882 (72.6%) 1779 (59.8%) 0.0001
Nodular goiter 1089 (26%) 271 (22.3%) 818 (27.5%) 0.0006
Autoimmune thyroiditis 316 (7.5%) 24 (2.0%) 292 (9.9%) 0.0001
Graves’ disease 91 (2.2%) 25 (2.1%) 66 (2.2%) NS (0.8)
Toxic adenoma 30 (0.7%) 13 (1.1%) 17 (0.6%) NS (0.1)
Neck irradiationa 119/3898 (3.2%) 63/1021 (6.1%) 56/2877 (1.9%) 0.0001
NS, Not significant.
a
Information on the radiation exposure was not available in 289 patients: 194 of group 1 and 95 of group 2.


TABLE 3. Prevalence of presenting symptoms in the entire group (total series) and separately in patients diagnosed
before 1990 (group 1) and after 1990 (group 2)
No. of patients with available data 3997 1175 2822
Presenting symptoms (n)
Thyroid nodule 2670 (66.8%) 772 (65.7%) 1898 (67.3%) NS (0.3)
Incidental finding 657 (16.4%) 94 (8.0%) 563 (20.0%) 0.0001
Cervical nodes 396 (9.9%) 200 (17.0%) 196 (7.0%) 0.0001
Local symptoms 134 (3.4%) 58 (5.0%) 76 (2.6%) 0.0005
Hyperthyroidism 104 (2.6%) 30 (2.5%) 74 (2.6%) NS (0.9)
Distant metastases 36 (0.9%) 21 (1.8%) 15 (0.5%) 0.0003
This clinical information was not available in 190 patients: 40 of Group 1 and 150 of Group 2. NS, Not significant.

the new TNM classification) was relatively common the total series and particularly in group 2, which did
and more frequently found in group 2 than in group 1 not reach 2.0% as opposed to the almost 7.0% in group
(19.8 vs. 18.3%). Conversely, macroinvasion (i.e. T4 in 1. In this context, it may be relevant to point out that
the new TNM classification) was much less frequent in micro-PTC (mPTC) are often localized close to the thy-

TABLE 4. Prevalence of several pathological features in the entire group (total series) and separately in patients
diagnosed before 1990 (group 1) and after 1990 (group 2)
Tumor size: N 3996 1100 2896
1 cm (mPTC) 923 (23.1%) 87 (7.9%) 836 (28.7%) 0.0001
1 to 2 cm 1132 (28.3%) 389 (35.4%) 743 (25.8%) 0.0001
2 to 4 cm 1409 (35.3%) 432 (39.3%) 977 (33.7%) 0.002
4 cm 532 (13.3%) 192 (17.4%) 340 (11.8%) 0.0001
Local extension: N 3625 824 2774
No extrathyroid 2967 (81.8%) 673 (81.7%) 2267 (81.7%) NS (0.4)
Extrathyroid 658 (18.2%) 151 (18.3%) 507 (18.3%)
T3 (microinvasion) 545 (15.0%) 93 (11.3%) 452 (16.3%) 0.002
T4 (macr-invasion) 113 (3.1%) 58 (7.0%) 55 (1.9%) 0.0001
Lymph nodes metastases
N 4184 1213 2971
n 1081 (25.8%) 415 (34.2%) 666 (22.4%) 0.0001
Distant metastases
N 4184 1213 2971
n 127 (3%) 66 (5.4%) 61 (2%) 0.0001
Clinical classes (De Groot’s
classification)
N 3995 1102 2893
n
I 2450 (61.3%) 542 (49.2%) 1908 (65.9%) 0.0001
II 764 (19.1%) 332 (30.1%) 432 (14.9%) 0.0001
III 655 (16.4%) 163 (14.8%) 492 (17%) NS (0.1)
IV 126 (3.2%) 65 (5.9%) 61 (2.2%) 0.0001
Stage (VI TNM classification)
N 4109 1179 2930
n
I 2736 (66.6%) 761 (64.5%) 1975 (67.4%) NS (0.07)
II 615 (15%) 151 (12.8%) 464 (15.8%). 0.01
III 345 (8.4%) 127 (10.8%) 218 (7.4%) 0.0005
IVA 177 (4.3%) 56 (4.7%) 121 (4.1%) NS (0.4)
IVB 141 (3.4%) 35 (3.0%) 106 (3.6%) NS (0.3)
IVC 95 (2.3%) 49 (4.2%) 46 (1.7%) 0.0001
Multifocality
N 3726 896 2830
n 1354 (36.0) 283 (31.5%) 1071 (37.8%) 0.0008
Bilaterality
N 3662 873 2789
n 730 (19.9%) 134 (15.3%) 596 (21.4%) 0.0001
N, Number of patients with available data for each pathological feature; n, number of patients with the pathological feature; NS, not significant.


roid capsule and had a limited microscopic extrathy- 0.0001). This was not related to the longer follow-up time
roidal extension (3, 30, 31). Thus, despite being asso- in group 1 because the difference remained significant
ciated with a good prognosis, these tumors fulfilled the even when the survival data were analyzed by comparing
definition of a tumor with local extension, thus increas- populations within the two groups with equal follow-up
ing the percentage of T3 tumors. Lymph node metasta- periods.
ses were present in 25.8% of the total series, whereas Survival curves obtained by univariate analysis of sev-
only 3.0% of the cases showed distant metastases. Both eral prognostic factors in the total series are reported in
lymph node and distant metastases were significantly Fig. 3. Prognosis was influenced by gender as shown by the
less frequent in group 2 (22.4 and 2.0%, respectively) significant, albeit small, reduction of survival observed in
than in group 1 (34.2 and 5.4%, respectively). To a large males compared with females (Fig. 3A). As shown in Fig.
extent, similar changes were observed in the class dis- 3B, the influence of age was analyzed by subdividing the
tribution, with a significant increase of class I (49.2 vs. patients into three age ranges. Almost all patients younger
65.9%) and a decrease of classes II (30.1 vs. 14.9%) and than 41 yr at diagnosis survived until the end of follow-up.
IV (5.9 vs. 2.2%) in group 2. As shown in Table 4, There was a significant decrease of survival in patients
similar results were observed when patients were clas- 41– 60 yr old [odds ratio (OR) 11.26] and a much
sified according to the sixth edition TNM classification greater decrease in those older than 60 yr (OR 49.2).
which, at variance with the De Groot’s classification, Patients with FTC had a significantly less favorable out-
takes into account both the extension of the disease and come than those with PTC (Fig. 3C). A tumor size greater
the age of patients at diagnosis (22). It is worth noting than 4 cm appeared to be an unfavorable prognostic factor
that the percentage of locally advanced cases without for survival, whereas no differences were observed in the
distant metastases, which are included in class III in the survival of patients with smaller tumors (Fig. 3D). Local
De Groot’s classification and in stage IVA and IVB in the extrathyroidal extension had a significant negative influ-
TNM classification, did not change in the two groups of ence on survival, but only when T4 (macroinvasion) was
patients. Both multifocality and bilaterality showed an considered separately from T3 (microinvasion) (Fig. 3E).
increase in group 2 (37.8 and 21.4%, respectively) when The presence of lymph node metastases was found to have
compared with group 1 (31.5 and 15.3%, respectively). a small but significant negative influence (Fig. 3F). The
The mean follow-up of the total series was 9 7.6 yr presence of distant metastases was the most impressive
(range 0.5–34.5 yr, median 7 yr). A total of 2576 patients poor prognostic factor for survival, with only 50% of met-
had a follow-up of at least 5 yr, 1547 at least 10 yr, and 507 astatic patients surviving after 10 yr (Fig. 3G). When the
at least 20 yr. There was a marked difference in the fol- clinical stage was considered, a progressive decrease in
low-up period between group 1 (range 1–34.5; median survival was observed with the increasing number of the
19.5 yr) and group 2 (range 1–14.9; median 5.5 yr). class, and class IV was the most unfavorable one (Fig. 3H).
The survival rate of DTC patients is shown in Fig. 2. At
Neither multifocality nor bilaterality had any significant
the end of the follow-up, the percentage of survivors in the
influence on survival (data not shown).
total series was 96.4%, and there was a significant differ-
Survival curves in relation to prognostic factors were
ence between group 1 and group 2 (91.4 vs. 98.7%) (P
also studied separately in the two groups by univariate
analysis (Fig. 4). Essentially the same pattern of the total
series was observed in both groups. To a variable extent,
however, the survival rate was more affected in group 1 for
all prognostic factors except for the presence of metastatic
lymph node, which showed a small but significant influ-
ence on survival in group 2 but not in group 1 (Fig. 4F).
The prognostic factors found to be significant in the
univariate analysis were submitted to the multivariate
analysis (Table 5). Gender and tumor size were found to
have no independent influence on survival in either the
total series or in the two groups. Conversely, age at diag-
FIG. 2. Survival curves of patients with DTC. The overall survival of the
total series was 96.4% after a 35-yr follow-up. A significant difference nosis resulted to be a significant independent poor prog-
was observed in the survival rate of group 1 and group 2 patients (P nostic factor both for the total series and for the two
0.0001). This was not related to the considerably longer follow-up of groups with high OR especially for patients over 60 yr of
group 1 with respect to group 2, because the difference remained
significant even when the survival data were analyzed by comparing age. Histotype was found to independently influence the
subsets of the two groups with equal follow-up periods. survival when analyzed in the total series of patients and


terestingly, in the multivariate analysis,
the time period of the diagnosis (i.e. be-
fore 1990 or after 1990) was found to be
an independent prognostic factor. Pa-
tients diagnosed after 1990 had a signif-
icantly higher survival rate when com-
pared with those diagnosed before 1990.

Discussion
We analyzed clinical and pathological
features and prognostic patterns of
4187 consecutive DTC patients re-
ferred to our institution between Octo-
ber 1969 and December 2004. To our
knowledge, this is the largest series of
DTC patients treated at a single institu-
tion using standardized therapeutic and
follow-up protocols and having a re-
markably low loss at follow-up. We felt it
would be interesting to subdivide the to-
tal series into two groups according to the
time period of diagnosis: group 1 with
1215 patients and group 2 with 2972 pa-
tients observed before and after 1990, re-
spectively. The rationale to choose the
year 1990 was related to the widespread
use of neck ultrasound and the introduc-
tion of other sensitive diagnostic tools
that happened around that year.
We found a similar age at diagnosis
in the two groups, and this finding
was consistent with those of Farahati
et al. (5) and Chow et al. (9), who after
subdividing their series into three
groups according to the year of diag-
nosis, failed in finding differences in
FIG. 3. Survival curves of the total series of 4187 patients with DTC according to the different
clinical and pathological features: gender (A), age at diagnosis (B), histotype (C), tumor size (D),
the mean age at diagnosis. Still in
local extrathyroidal extension (E), lymph node metastases (F), distant metastases (G), and De keeping with our results, they also ob-
Groot’s clinical classification (H). All of these variables showed a significant prognostic role. served a slight increase in the percent-
age of DTC in males over the years.
in group 1 but not in group 2. Local extrathyroidal ex- Such an increase in males could be
tension barely reached a level of significance in the total partially explained by the fact that thyroid nodules are
series and in group 2 but was not significant in group 1. clinically not easy to be appreciated in males, whereas
The same pattern was observed when T3 and T4 cases were they can be found by ultrasound (32). Indeed, the inci-
separately analyzed (data not shown). The presence of dental discovery of a thyroid nodule by Doppler sonog-
lymph node metastases was found to have a significant raphy performed during the work-up of hypertension or
negative influence on the survival rate both in the total other cardiovascular diseases is the most common medical
series and, to a lesser extent, in the two groups. Class III context in which thyroid nodules are found in middle-aged
and mainly class IV were associated with a markedly poor men (33).
prognosis in all groups, whereas classes I and II were found We observed an increase of PTC accompanied by a
to have no influence on the survival of DTC patients. In- relevant decrease of FTC in group 2. This pattern is con-


ciation between a high prevalence of
BRAF V600E mutation, which is the
most common genetic alteration in PTC
(38), and an elevated iodine intake has
been reported and interpreted as a pos-
sible link between iodine exposure and
the development of PTC (39). Another
explanation of this increased ratio
could be the greater attention to the his-
tological pattern of the follicular vari-
ant of PTC. Albores-Saavedra et al.
(40) reported that the rate of this vari-
ant increased by 173% between 1973
and 2003. They considered this as the
major contributing factor underlying
the increase of PTC in the last decades.
We made an effort to reduce this bias by
reassessing the histotype of the tumors
diagnosed before the middle of the
1980s, but unfortunately, this could not
be done in all cases. Finally, the relative
fall in the percentage of FTC cases in
group 2 could be the result of the in-
creased detection of small thyroid can-
cer, most of which are PTC (2).
The presence of a coexisting thyroid
disease, in particular of a nodular goiter
and thyroid autoimmunity, was more
frequently observed in group 2. Regard-
ing this, the role of the neck ultrasound
appears of great relevance for the pos-
sibility of detecting both uni- or multi-
nodular small nodular goiter and per-
forming echo-guided FNA of these
small nodules as opposed to the clinical
approach that limited FNA to the dom-
inant nodule (41). Neck ultrasound
played also an important role in the di-
FIG. 4. Survival curves of group 1 (1969 –1989, red lines) and group 2 (1990 –2004, black
agnosis of thyroiditis, which has been
lines) patients (univariate analysis) according to their clinical and pathological features. To a demonstrated to have a specific hypo-
variable extent, survival rate was more affected in group 1 for all prognostic factors except for echoic ultrasound pattern (42), not clin-
the presence of lymph node metastases, which had a small but significant influence on ically identifiable. Another possible ex-
survival in group 2 but not in group 1 (F).
planation for the higher percentage of
thyroiditis in group 2 is the increased
sistent with previous reports (1–3, 6), and several expla- attitude to measure serum thyroid antibodies during the
nations may be offered for its occurrence. A shift in the work-up of thyroid diseases. However, there are data
PTC/FTC ratio in favor of PTC is a well-recognized effect showing also a true increase of thyroiditis that has been
of iodine prophylaxis (34, 35). This phenomenon was also attributed to environmental factors, including an increase
observed by Belfiore et al. (36) in Sicily. Because a signif- in iodine intake (43), which, as aforementioned, has hap-
icant decrease of iodine deficiency has been observed in pened also in our country in the recent years (37).
Italy in the recent years (37), we can assume that it could External radiation to the head and neck was frequently
have contributed to the increase of the PTC to FTC ratio. used for the treatment of benign diseases in children and
Regarding this, it is worth noting that, recently, an asso- adolescents up until the early 1960s. This was before the


TABLE 5. Multivariate analysis of prognostic variables in the entire group (total series) and separately in patients
diagnosed before 1990 (group 1) and after 1990 (group 2)
Total series Group 1 Group 2
Variables SE P OR SE P OR SE P OR
Gender
Male vs. female 0.44 0.26 0.095 1.55 0.57 0.36 0.113 1.77 0.43 0.42 0.300 1.55
Age (yr)
41– 60 vs. 40 2.42 0.62 0.0001 11.26 2.95 1.04 0.005 19.20 1.93 0.80 0.016 6.92
60 vs. 40 3.89 0.61 0.0001 49.20 4.53 1.03 0.0001 93.56 3.11 0.79 0.0001 22.52
Histotype
PTC vs. FTC 0.95 0.27 0.001 0.38 1.44 0.35 0.0001 0.23 0.05 0.56 0.919 1.06
Tumor size (cm)
1–2 vs. 1 0.85 0.45 0.062 0.42 0.40 0.66 0.543 0.66 1.51 0.83 0.069 0.22
2– 4 vs. 1 0.24 0.41 0.562 0.78 0.10 0.63 0.870 0.90 0.01 0.59 0.978 1.01
4 vs. 1 0.71 0.39 0.068 2.03 0.97 0.60 0.104 2.65 0.79 0.56 0.170 2.21
Local extrathyroidal extension 1.09 0.54 0.045 0.33 0.89 0.89 0.316 0.40 1.47 0.73 0.045 0.22
(with vs. without)
Lymph node metastases 1.50 0.37 0.0001 4.51 1.08 0.52 0.041 2.9 1.42 0.57 0.014 4.1
(with vs. without)
De Groot’s class
2 vs. 1 0.14 0.54 0.979 1.01 0.45 0.74 0.538 1.58 0.24 0.87 0.778 1.27
3 vs. 1 1.78 0.59 0.003 5.96 1.80 0.90 0.045 6.05 2.21 0.90 0.015 9.17
4 vs. 1 2.89 0.38 0.0001 18.07 2.38 0.47 0.0001 10.84 3.98 0.73 0.0001 53.54
Year of diagnosis: 1990 0.88 0.26 0.001 0.41
vs. 1990

recognition of the associated risk of radiation-induced marked increase in small PTCs. In particular, mPTC ac-
thyroid cancer (44). The relatively high percentage of pa- counted for almost 30% in group 2, as opposed to 8% in
tients with a positive history of radiation exposure to the group 1. An increase of small tumors has been reported in
neck in group 1 (6.1%) was consistent with the rather long other series recently published, and an increased incidence of
latency period of radiation-induced thyroid cancer (45). In mPTC has been specifically stressed by several authors (1–3,
patients of group 2, however, a much lower percentage 10). The question remains as to whether the reduced aggres-
was found (1.9%). This was related to the discontinuation siveness and size of tumor more recently diagnosed are due
of external radiation use in children and adolescents. to diagnosis in an early phase of development or whether it
The majority of patients in both groups presented with is due to the identification of a small thyroid carcinoma that
thyroid nodules, but it is worth noting that as many as would have otherwise never become clinically evident.
20% of those referred after 1990 found the nodule during Although further studies are needed to clarify this issue, it
diagnostic procedures (usually a neck ultrasound) per- may be noted that in this series, as well as in the majority
formed for reasons other than thyroid-related disorders of series reported on mPTC (46), both the mean and me-
including an extension of gynecological and mammary dian age of the two groups of patients were essentially the
gland work-up, metabolic assessment preceding a weight same. This finding contradicts the simple hypothesis of an
loss program, or color Doppler evaluation of the neck for early diagnosis and is consistent with the concept that
evaluation of carotid vascular disease. many, albeit not all, small thyroid carcinomas may remain
Larger tumors, lymph nodes, and/or distant metastases silent over the entire lifespan, as indicated by the finding
were less frequent in group 2 than in group 1. Classes III of small thyroid tumors at autopsy in many subjects who
and IV, which included the most severe cases, were also had died due to unrelated causes (47, 48). Nevertheless,
significantly less represented in group 2. Similar results the significantly lower percentage of patients with lymph
have been observed by Chow et al. (9), who found a de- node and/or distant metastases at the time of diagnosis in
crease in the percentage of patients with positive lymph group 2 strongly support the hypothesis of an anticipation
nodes and/or distant metastases in the more recent period of diagnosis at least of advanced cases that, in the past,
of observation. An earlier diagnosis, probably due to the would have been found at a much later point with physical
increased use of more sensitive diagnostic procedures such examination or chest radiography.
as neck ultrasound and Tg measurement in FNA (17), is In contrast with a significant increase of intrathyroidal
the most reasonable explanation of this finding. tumors (i.e. class I or stage I) and the decrease of both
In the present study, the reduced percentage of more ag- lymph node (i.e. class II or stage II and III) and distant
gressive tumors observed in group 2 was associated with a metastases (i.e. class IV or stage IVC), we did not observe


a corresponding decline of the locally advanced DTC (i.e. was very similar during the years studied, and we prefer
class III or stage IVA and IVB) in group 2. This finding is the hypothesis that an earlier identification of both the
similar to that reported by Enewold et al. (10) and evokes primary tumor and recurrence is the reason of the better
the question of why the prevalence of DTC with local outcome of group 2 patients.
invasiveness did not change during the time studied. A In conclusion, the present study, although based on
possible simplified explanation is that the cellular growth cases referred to our institution and not on all Italian DTC
rate of these groups of DTC is so high that it is almost cases, confirms and extends data indicating a marked
impossible to anticipate their diagnosis. Only a complete change in clinical and pathological features of DTC oc-
molecular characterization of DTC tumors with different curring in recent years. The most relevant aspect is the
biological behavior could better explain these clinical ob- sharp increase in the proportion of PTCs of smaller size,
servations (49). especially mPTC, in patients diagnosed after 1990. In par-
Local extrathyroidal extension showed no difference allel, a relative reduction of more advanced cases was also
between the two groups of patients. This finding is in ap- observed in this group. The smaller proportion of patients
parent contrast with data indicating that most indices of free from other thyroid disorders, but particularly of those
severity of thyroid cancer were less frequent in group 2. in whom the thyroid lesion was an incidental finding of
According to data reported by both Gemsenjager et al.
¨ diagnostic procedures for other conditions, is consistent
(50) and Hu et al. (51) macro (i.e. T4) but not micro (i.e. with the suggestion that the increasing use of ultrasound
T3) extrathyroidal extension represents a risk factor for a procedures is largely responsible for the recognition of
lower survival. When we analyzed separately T3 and T4 in clinically silent thyroid diseases, especially thyroid nod-
our two groups of patients, we found that macro-extra- ules of small/medium size. Taken together, these observa-
thyroidal extension was, as expected, significantly less fre- tions may suggest that the increased attention and larger
quent in group 2. use of sensitive diagnostic techniques, such as neck ultra-
Both multifocality and bilaterality were more frequent sound, result in the detection of tumors at an earlier stage.
in group 2. This finding could be related to the changed This interpretation is not consistent with the finding that
methodology used in the pathological assessment, with the mean age at diagnosis of patients observed before and
particular regard to the greater number of samplings per- after year 1990 was unchanged. However, we can explain
formed after the 1980s. Nevertheless, neither bilaterality the two apparently conflicting results with the introduc-
nor multifocality appeared to influence the survival of our tion of neck ultrasound and the general improvement of
patients. This finding is in keeping with other reports (52– diagnostic tools that determined both the discovery of a
54) and confirms our previous observation that both mul- great number of clinically silent mPTC and the early di-
tifocality and bilaterality may affect the local recurrence agnosis of metastases and recurrences. Irrespective of
but not the survival (55). these very important changing features and the improved
general outcome of DTC patients diagnosed in the recent
Gender, age, histotype, tumor size, local macro-extra-
years, older age and advanced stage still remain the two
thyroidal extension, lymph nodes, and distant metastases
most unfavorable prognostic factors for a lower survival
as well as clinical classes were found to have a significant
and must be taken into consideration in planning the ther-
negative influence on survival in univariate analysis of the
apeutic strategy.
total series. When these prognostic factors were analyzed
separately in group 1 and group 2, similar qualitative re-
sults were obtained. However, in the multivariate analy-
sis, only age and clinical class were found to retain their Acknowledgments
independent prognostic values. As shown in Table 5, pa- We thank all colleagues who participated in this study, in par-
tients older than 60 yr or those with a class IV tumor, ticular Marco Capezzone, Filomena Cetani, Francesco Mancusi,
which included all cases with distant metastases, showed Riccardo Lari, Rosanna Bonacci, and Maria Angela Sculli, who
the higher risk in terms of OR value. collaborated in the database collection; Donatella Taddei, Clau-
Of interest is the finding that the year of diagnosis dia Mammoli, Mariella Ciampi, and Tamara Giacomelli who
showed a significant independent influence on the survival performed the majority of laboratory assays; Piero Berti and
rate in the multivariate analysis. Patients diagnosed and Gabriele Materazzi, who collaborated for surgical treatment;
treated after 1990 had a better outcome. The two most Clara Ugolini and Pinuccia Faviana, who collaborated for patho-
logical review of slides; and Gaetano Privitera and Mario Miccoli
reasonable explanations of this more favorable outcome
for their statistical support.
are the early diagnosis and the more effective treatment
developed in the recent years. However, as stated in the Address all correspondence and requests for reprints to:
introductory section, in our series, the therapeutic strategy Rossella Elisei, M.D., Department of Endocrinology, University of


Pisa, Via Paradisa 2, 56124 Pisa, Italy. E-mail: relisei@endoc. B, Cailleux AF, Lumbroso JD, Parmentier C, Schlumberger M 1998
med.unipi.it. Microcarcinoma of the thyroid gland: the Gustave-Roussy Institute
This work has been supported in part by grants from Asso- experience. Cancer 83:553–559
ciazione Italiana Ricerca sul Cancro (AIRC), Ministero della 16. Rago T, Vitti P, Chiovato L, Mazzeo S, De Liperi A, Miccoli P,
Viacava P, Bogazzi F, Martino E, Pinchera A 1998 Role of con-
Istruzione Universitaria e Ricerca Scientifica (MIUR), Istituto
ventional ultrasonography and color flow-doppler sonography in
Toscano Tumori (ITT), and Ministero della Salute, Progetto
predicting malignancy in ‘cold’ thyroid nodules. Eur J Endocrinol
Ricerca Oncologica RF-CAM 2006353005. 138:41– 46
A.P. has access to all of the data in the study and takes re- 17. Pacini F, Fugazzola L, Lippi F, Ceccarelli C, Centoni R, Miccoli P,
sponsibility for the integrity of the data and accuracy of the data Elisei R, Pinchera A 1992 Detection of thyroglobulin in fine needle
analysis. F.P. was in Pisa at the Department of Endocrinology aspirates of nonthyroidal neck masses: a clue to the diagnosis of
until October 2002. metastatic differentiated thyroid cancer. J Clin Endocrinol Metab
Disclosure Summary: The authors have nothing to disclose. 74:1401–1404
18. Mazzaferri EL, Robbins RJ, Spencer CA, Braverman LE, Pacini F,
Wartofsky L, Haugen BR, Sherman SI, Cooper DS, Braunstein GD,
Lee S, Davies TF, Arafah BM, Ladenson PW, Pinchera A 2003 A
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